The physiological and immunological alterations induced in patients undergoing interventive cardiac surgery necessitating cardiopulmonary bypass (CPB) have been well established in recent years. The sequential elevation of systemic cytokine levels have also been shown to result in the depletion of cardiac myocyte amino acids such as taurine and in an in vitro model the reduction in ICAM-1 expression on endothelial cells. Studies showed that post reperfusion taurine levels were low in both blood and crystalloid cardioplegia patients.
The most important of the initiating stimuli responsible for the release of such proinflammatory mediators is debated; however, the development of a systemic endotoxemia is considered to be a significant prognostic factor. It is well established that endotoxin (or lipopolysaccharide), itself a bacterial cell wall product, has been recognized as a potent proinflammatory cell activator both in vivo and in vitro. A systemic endotoxemia has been clearly demonstrated to occur in patients undergoing CPB. This occurs following the release of the aortic cross clamp. The pathophysiological mechanism underlying this endotoxemia has been suggested as being secondary to bacterial translocation following inadvertent gut ischemia. The efficacy of the host response to this endotoxemia has direct implications for the development of postoperative morbidity. A low preoperative titer of IgM anti-endotoxin core antibody has been used as an independent prognostic indicator of host outcome following CPB in one study, thus emphasizing the significance of endotoxin. Another group suggested that the interleukin-6 (IL-6) systemic elevation, which also occurs in CPB patients, is a direct consequence of this early systemic endotoxemia and may in turn be responsible for the post-reperfusion sequelae. One group in particular suggested that the major cause of reperfusion injury is through the iron mediated generation of the hydroxyl radical (OH). They demonstrated that the use of highly diffusible desferri-exochelins block injury caused by OH production and have potential for the treatment of reperfusion injury.
Taurolidine (bis(1,1-dioxoperhydro-1,2,4-thiadiazin-4-yl)methane) has been employed as a clinically effective therapeutic agent for many years. The compounds taurolidine and taurultam are as disclosed in U.S. Pat. No. 5,210,083, incorporated herein by reference. Taurolidine has been utilized both for antibacterial prophylaxis and as a therapeutic bactericidal agent in peritoneal sepsis. It has a short half life and is rapidly metabolized to taurine, carbon dioxide and water. Taurolidine has been shown to have a broad spectrum of antimicrobial activity against both gram positive and gram negative bacteria and fungi and has a neutralizing activity against bacterial endotoxin. There is no definite treatment available for reperfusion injury. Taurine, one of the key metabolites of taurolidine, has been shown to possess significant therapeutic properties of its own including endothelial cell membrane stabilization, proinflammatory cell antiapoptotic and antioxidant capability and homeostatic cellular osmoregulation. In some animal studies results indicated that taurine protects ischemic heart muscle against reperfusion induced arrhythmias, through its properties both as a membrane stabilizer and an oxygen free radical scavenger. Taurolidine has been shown to be non-toxic to humans and animals and is free from side effects following intravenous and intraperitoneal administration. This wide spectrum of antiseptic properties has led to its clinical application in conditions ranging from osteomyelitis to peritonitis and catheter related sepsis prophylaxis.
In accordance with the present invention, a method of reducing postoperative complications of cardiopulmonary bypass (CPB) surgery in a patient comprises administering to the patient an effective amount of a methylol transfer agent in conjunction with CPB surgery of said patient.
To prevent postoperative complications, in particular damage of the myocardium by reperfusion, e.g., arrhythmia, intravenous administration of taurolidine or taurultam solutions is performed intraoperatively.
Disturbances of the rhythmic center and conduction system of the heart due to formation of myocardium-damaging peroxides during reperfusion may lead to sinus-arrhythmia, ventricular-fibrillation and fluttering. Such complications can be avoided by intraoperative intravenous administration of taurolidine or taurultam solutions.
An additional effect is the protection from much feared infections and toxemia such as streptococci, enterococci, klebsiella, pseudomonas and serratia, inclusive of mycotic infections as candida or aspergillus, for prevention of acute myocarditis, pericarditis and endocarditis.
Intraoperative dosages may be in the range of about 10-20 grams taurolidine or taurultam as active ingredient, or combination of both substances in about a 2% hypotonic solution or in about a 1% isotonic Ringer""s solution as drop infusion via a central vein catheter.
The present invention is applicable to any suitable methylol transfer agent that reduces postoperative complications of CPB surgery in a patient. Although the invention is further described with respect to the methylol transfer agents Taurolidine and/or Taurultam, it is to be understood that the invention is equally applicable to any suitable methylol transfer agent having activity similar to or substantially the same as Taurolidine and/or Taurultam.
Methylol transfer agents in accordance with the present invention can be administered in any suitable form, such as orally administered tablets or capsules, or intravenously administered solutions.
In preferred embodiments, 250 ml of Taurolidine 2% solution is administered by intravenous infusion about 1-6 times per day, more preferably about 2-4 times per day during the treatment period.
One or more methylol transfer agents in accordance with the present invention can be administered before, during and/or after CPB surgery.
In accordance with preferred embodiments, 2% Taurolidine solution is administered by intravenous infusion to a CPB patient during surgery, and the patient receives about 250 ml doses per day at about 12 hour intervals following the CPB surgery.
In accordance with one embodiment, perioperative administration of the anti-endotoxins taurolidine and/or taurultam is utilized in the attenuation of the post-reperfusion sequelae in patients subjected to cardiopulmonary bypass. It is believed that the invention may affect:
(i) reduction of septic complications following CPB;
(ii) reduction of reperfusion induced arrhythmias in blood cardioplegia and crystalloid cardioplegia patients;
(iii) amelioration of systemic endotoxemia and proinflammatory cytokine activation in the perioperative period; and
(iv) reduction in respiratory compromise seen in post CPB patients.
In preferred embodiments, the present invention utilizes an established non-toxic antiseptic, antiendotoxin and antioxidant agent such as taurolidine and/or taurultam in the amelioration of the post operative physiological morbidity associated with CPB surgery. In preferred embodiments, the present invention utilizes perioperative taurolidine in the clinical setting of cardiac surgery to impact post-operative reperfusion induced arrhythmias, sepsis, inotropic support and in turn early mobilization and reduction in the hospital stay and improvement of clinical prognostic indicators in patients undergoing CPB with both crystalloid and blood cardioplegia techniques.
It is believed that through the therapeutic amelioration of the early systemic endotoxemia seen in CPB patients, attenuation of the proinflammatory mediator cascade may be achieved. This is believed to result in a reduction in the postoperative cytokine mediated sequelae, and ultimately result in an improved clinical outcome of CPB patients.
Aortic unclamping during cardiopulmonary bypass is the ultimate ischemia reperfusion injury and is characterized by marked derangement of the systemic inflammatory response (SIRS). Taurolidine, a potent anti-inflammatory antioxidant, has proven efficacy in patients with SIRS following pancreatitis. This invention shows the benefits of taurolidine treatment in patients subjected to CPB.
The present invention is described by reference to the following Examples, which are offered by way of illustration and are not intended to limit the invention in any manner. Standard techniques well known in the art or the techniques specifically described below were utilized.